Sphingolipids have historically been studied in the setting of rare genetic disorders where these compounds accumulate due to a defect in an enzyme or activator for their metabolism. However, more recent studies have identified several potential functional roles for sphingolipids, including mediators of intracellular signaling events or of cell-cell interactions. From these studies it has been proposed that sphingolipids play a role in the pathophysiology of more common disorders such as cancer or infection. We have studied the role of sphingolipids in another common disorder, diabetes mellitus, and have observed that hyperglycemia results in increased levels of renal glycosphingolipids in concert with the early hypertrophic changes of diabetic nephropathy. Hyperglycemia-induced changes in renal glycosphingolipid formation are observed in both the kidneys of streptozotocin-treated rats and in renal proximal tubule cells. Pharmacological inhibition of glucosylceramide synthesis reverses the early renal hypertrophy in diabetic kidneys and the proliferative response of proximal tubular epithelial cells cultured in hyperglycemia medium, consistent with the existence of a biochemical link between glycosphingolipids and diabetic nephropathy. We propose as the major hypothesis for this grant that the renal growth accompanying early diabetic hypertrophy is mediated by altered sphingolipid metabolism. The specific aims of this proposal are: 1. To characterize the nature of the relationship between hyperglycemia and the rate of glycosphingolipid synthesis. 2. To define the role of individual sphingolipids in mediating the growth response to hyperglycemia. 3. To determine the role of changes in sphingolipid content in regulating IGF-1-stimulated cellular proliferation and cell cycle progression.